{"entity":{"id":"idea-tr2-marker-stratified-default","kind":"idea","name":"Test the drug in biomarker-negative patients too, so the biomarker can be validated","aka":[],"tldr":"Trials that only enrol patients with a positive biomarker can never prove the biomarker matters. Including a smaller biomarker-negative group would show whether the test is really needed.","summary":"Enrichment designs enrol only biomarker-positive patients and cannot estimate the interaction between marker and treatment. Marker-stratified designs (all-comers with stratified randomisation and pre-specified interaction tests) are the accepted way to validate a predictive biomarker but are rarely used because they cost more. Regulators could require a marker-negative cohort (even under-powered but pooled across trials) whenever a biomarker is proposed to restrict a label, so the restriction is evidence-based.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Biomarkers are not validated or standardised): Fernandez et al., Examination of low ERBB2 protein expression in breast cancer tissue (JAMA Oncology 2022)","url":"https://doi.org/10.1001/jamaoncol.2021.7239"}],"tags":[],"related":["hrd","her2-low","idea-tr2-biomarker-negative-arms"],"cancers":[],"sections":[],"technologies":["companion-diagnostic"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["companion-diagnostic-term","hazard-ratio"],"trials":[],"people":[],"bottlenecks":["b-biomarker-validation","b-trial-design"],"keyPapers":["paper-fernandez-jama-oncol"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Among drugs approved with a biomarker restriction, marker-negative cohorts will show clinically meaningful benefit in at least a fifth of cases, revealing that current enrichment designs deny treatment to patients who would benefit.","rationale":"PD-L1 cut-offs, HER2-low, and HRD have each shifted after post hoc analyses of marker-negative or unselected populations, showing that enrichment-only evidence leads to unstable labels.","test":"Fund marker-negative cohorts in five ongoing enrichment trials and analyse interaction effects; compare with historical label revisions.","maturity":"early-clinical","actor":"regulator","cost":"medium","horizonYears":4},"route":"/ideas/idea-tr2-marker-stratified-default/","neighbours":{"term":[{"id":"companion-diagnostic-term","kind":"term","name":"Companion diagnostic","route":"/terms/companion-diagnostic-term/"},{"id":"hazard-ratio","kind":"term","name":"Hazard ratio (HR)","route":"/terms/hazard-ratio/"},{"id":"her2-low","kind":"term","name":"HER2-low and HER2-ultralow","route":"/terms/her2-low/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"}],"idea":[{"id":"idea-tr2-cutpoint-lock","kind":"idea","name":"Lock the biomarker cut-off before phase 3, and publish it","route":"/ideas/idea-tr2-cutpoint-lock/"},{"id":"idea-tr2-biomarker-negative-arms","kind":"idea","name":"Randomised trials to test whether biomarker-negative patients really do not benefit","route":"/ideas/idea-tr2-biomarker-negative-arms/"}],"technology":[{"id":"companion-diagnostic","kind":"technology","name":"Companion diagnostics","route":"/technologies/companion-diagnostic/"}],"bottleneck":[{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"paper":[{"id":"paper-fernandez-jama-oncol","kind":"paper","name":"Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue","route":"/key-papers/paper-fernandez-jama-oncol/"}],"roadmap":[{"id":"diagnostics-roadmap","kind":"roadmap","name":"Diagnostics roadmap: stains → gene panels → blood tests that decide treatment","route":"/roadmaps/diagnostics-roadmap/"}]}}